This application is directed to an improved process for making phosphodiesterase IV inhibitors such as those described in WO 94/14742, published Jul. 7, 1994.
Many hormones and neurotransmitters modulate tissue function by elevating intra-cellular levels of adenosine 3',5'-cyclic monophosphate (cAMP). The role of cyclic AMP (cAMP) as a second messenger is well recognized. It is responsible for transducing the effects of a variety of extracellular signals, including hormones and neurotransmitters. The level of intracellular cAMP is regulated through both its synthesis by adenyl cyclases and degradation by cyclic nucleotide phosphodiesterases (PDE). PDEs form a family of at least seven enzyme isotypes (I-VII) which differ in their affinity for cAMP and/or cGMP, subcellular localisation and regulation (Beavo J. A. and Reifsnyder D. H. (1990) Trends Pharmacol. Sci. 11 150-155; Conti M. et al., (1991) Endocrine Rev. 12 218-234). The clinical effects of a number of drugs can be rationalised on the basis of their selectivity for a particular PDE isotype. For example, the cardiotonic drugs milrinone and zaprinast are PDE III and PDE V inhibitors respectively. (Harrison S. A. et al., (1986) Mol. Pharmacol. 29 506-514; Gillespie P. G. and Beavo J. (1989) Mol. Pharmacol. 36 773-781). The anti-depressant drug, rolipram functions as a selective PDE IV inhibitor. (Schneider H. H. et al., (1986) Eur. J. Pharmacol. 127 105-115.).
The availability of PDE isotype selective inhibitors has enabled the role of PDEs in a variety of cell types to be investigated. In particular it has been established that PDE IV controls the breakdown of cAMP in many inflammatory cells, for example, basophils (Peachell P. T. et al., (1992) J. Immunol. 148 2503-2510) and eosinophils (Dent G. et al., (1991) Br. J. Pharmacol. 103 1339-1346) and that inhibition of this isotype is associated with the inhibition of cell activation. Consequently PDE IV inhibitors are currently being developed as potential anti-inflammatory drugs particularly for the prophylaxis and treatment of asthma.
Nucleophilic conjugate additions to vinyl pyridines have received considerable attention over the last several decades. Heo, C. K. M. et al., J. Org. Chem. 1992, 57, 3570. The highly electrophilic double bond of this heterocycle has been used in a variety of applications such as: a pyridine-ethylenation agent for the indentification and/or purification of cysteine residues in on-line peptide sequencers, Kruft, V. et al., Anal. Biochem. 1991, 193, 306; a thiol protecting group, Katritzky, A. R. et al., J. Org. Chem. 1986, 51, 4914; a substrate in polymerization reactions useful in the rubber industry, Abraham, T. et al., patent WO 9109061 A2 910627; and a substrate in the synthesis of important pharmaceuticals, Chung, J. Y. L. et al., J. Org. Chem. 1996, 61, 3176.
There are a number of nucleophiles that react well with 4-vinylpyridine (or the 2-substituted derivative) ranging from soft nucleophiles, such as malonate anions, ester and amide anions, and aryl palladium reagents see Boekelheide, V. et al., J. Am. Chem. Soc., 1949, 71, 879; Boekelheide, V. et al., J. Am. Chem. Soc., 1951, 73, 2356 and Frank, W. C., et al, J. Org. Chem. 1978, 43, 2947. In contrast, addition of nucleophiles to substituted 4-vinyl pyridines has not received much attention.
A prior art process employs a synthetic strategy using 2S-bomane-010,2-sultan as a chiral auxiliary as shown below: ##STR2##
This method is not amenable to scale-up because of: a) it requires to many steps, b) the high price of the sultam; c) facile isomerization of the acid chloride during its preparation and/or the coupling reaction with the sultam, and d) extreme odor problem during the sultam cleavage using ethanethiol.
Another prior art process comprises treating the olefin 2, and a catalyst, nickel acetylacetonate, Ni(acac)2, with a slurry of the zincate, R.sup.1.sub.3 M, wherein M is ZnLi or ZnMgBr, followed by reductive removal of the sulfinyl group. ##STR3## R.sup.1 is phenyl, substituted phenyl, C.sub.1-6 alkyl or C.sub.2-6 alkenyl. This method also requires many steps.
Now, with the present invention there is provided a ready synthesis that produces Compound I in high yield. The process can be carried out in a few steps without the need for the introduction of activating groups.